Three-Dimensional Quantitative Structure−Activity Relationships of Cyclo-oxygenase-2 (COX-2) Inhibitors: A Comparative Molecular Field Analysis
| Autor: | Daniel Lesieur, Nicolas Baurin, Said Yous, Philippe Chavatte, Christophe Marot |
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| Rok vydání: | 2001 |
| Předmět: |
Models
Molecular Steric effects Molecular model Stereochemistry Quantitative Structure-Activity Relationship Cyclopentanes Thiophenes Field analysis Drug Discovery Benzene Derivatives Cyclooxygenase Inhibitors Pyrroles Spiro Compounds Topology (chemistry) chemistry.chemical_classification Binding Sites Cyclooxygenase 2 Inhibitors biology Bicyclic molecule Chemistry Imidazoles Isoxazoles Enzyme structure Isoenzymes Enzyme Cyclooxygenase 2 Prostaglandin-Endoperoxide Synthases Enzyme inhibitor biology.protein Pyrazoles Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 44:3223-3230 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to an extensive series of 305 varied diarylheterocyclic derivatives known as COX-2 selective inhibitors. X-ray crystal structure of COX-2 bound with SC-558, a selective COX-2 inhibitor, was used to derive the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (229 compounds) and subsequently validated with the corresponding test sets (76 compounds). The best predictive model (n = 229, q(2) = 0.714, N = 8, r(2) = 0.905, s = 0.291, F = 261.545) was selected for further comparison of the CoMFA contour maps obtained for steric, electrostatic, and lipophilic fields with the enzyme structure. The high level of compatibility with the COX-2 enzyme topology shows the great accuracy of this model that can predict inhibitory activities for a wide range of compounds and offers important structural insight into designing novel antiinflammatory drugs prior to their synthesis. |
| Databáze: | OpenAIRE |
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